It has been reported that melanocortins (α, β, γ-MSH, ACTH) are biosynthesized in the brain by processing pro-opiomelanocortin (POMC), a precursor thereof and involved in various physiological functions. Melanocortins express their physiological functions by binding to their specific receptors. Currently, the melanocortin receptors (MC receptors) are classified into five subtypes, MC1 to MC5. Of these receptors, the MC4 receptor is expressed specifically in the brain and extensively distributed in the brain.
Reports have suggested an association between the MC4 receptor and appetite and obesity. It has been reported that animal experiments using peptide agonists and antagonists selective to the MC4 and MC3 receptors show a potent inhibitory action on appetite in fasting mice and various obesity model animals (refer to Non-Patent Document 1).
Furthermore, marked increases in body weight and increases in blood insulin and glucose levels were observed in MC4 receptor knockout mice, suggesting that the MC4 receptor has an inhibitory action on eating behavior and obesity.
Meanwhile, in the brain, the MC4 receptor is widely distributed in the limbic system such as the hippocampus and the amygdala as well as raphe nuclei, the nuclei of origin of serotonin neurons, in addition to the hypothalamus, which is closely related to eating behavior. Furthermore, animal experiments have shown that ACTH and α-MSH act on regulation of body temperature, blood pressure, the neuroendocrine system, learning, memory, and arousal. Furthermore, it has been reported that they cause anxiety-like symptoms and activation of the hypothalamus-pituitary gland-adrenal gland system.
Recent reports have shown that MC4 receptor antagonists exhibit anxiolytic-like and antidepressant-like effects (refer to Non-Patent Document 2). Furthermore, since it has been suggested that HS014, an MC4 receptor antagonist, has efficacy in the stress-induced anorexia animal model (refer to Non-Patent Document 3), and the MC4 receptor is associated with functions regulating eating behavior and body weight, it is thought that MC4 receptor antagonists are effective for the treatment of cachexia in patients with cancer or AIDS or eating disorders such as stress-induced anorexia.
Furthermore, there have also been reports suggesting an association of the MC4 receptor with drug dependence (refer to Non-Patent Document 4) and pain (refer to Non-Patent Document 5).
The above findings are summed up that MC4 receptor antagonists are expected to be used as anxiolytic agents and antidepressants as well as therapeutic agents for eating disorders such as cachexia and anorexia or prophylactic or therapeutic agents for pain, drug dependence, and the like.
As MC4 receptor antagonists, piperazine derivatives have been reported (refer to Patent Documents 1 and 2).
Meanwhile, aminopyrrolidine derivatives have been reported in Patent Documents 3 and 4. However, aminopyrrolidine compounds encompassed in the technical scope of the present invention have not been reported, and relations between these compounds and the MC4 receptor have not been reported.    [Patent Document 1] WO02/00259    [Patent Document 2] WO03/053927    [Patent Document 3] WO03/028641    [Patent Document 4] WO02/068409    [Non-Patent Document 1] Nature, 385, 165, 1997    [Non-Patent Document 2] J. Pharmacol. Exp. Ther., 04(2), 818, 2003    [Non-Patent Document 3] Eur. J. Pharmacol., 369, 11, 1999    [Non-Patent Document 4] Eur. J. Neurosci., 21(8), 2233, 2005    [Non-Patent Document 5] Anesth. Analg., 93, 1572, 2001